THERAPEUTIC GASES PHARMACOLOGY AND IT’S ADVANCED DELIVERY

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Pharmaceutical gases molecules (Therapeutic medical Gases) are plays vital role in various disease conditions. In particular, Carbon monoxide, Oxygen, Nitric oxide, Hydrogen sulfide are generated in the human body and mediate signaling pathways as biological messengers and shown pharmacological effects on cardiovascular disorders, nervous system, respiratory track and gastrointestinal disorder. Appropriate oral delivery of gases is challenging concept in front of novel drug delivery system, recently microbubbles, nanobubbles, liposomes, ultrasound technology provides new oral and parenteral delivery platform for therapeutic gases. This review provides pharmacological effects of therapeutic medical gases and its novel delivery aspects.

INTRODUCTION

“Therapeutic medical gas is pharmaceutical gaseous molecules which offer solutions to medical needs.” Recent basic and clinical research has revealed that therapeutic gases is an important physiological regulatory factor with antioxidant, anti-inflammatory and anti-apoptotic protective effects on cells and organs. A therapeutic gas has been applied by different delivery methods including straight forward inhalation, drinking hydrogen dissolved in water and injection with hydrogen-saturated saline. The gases are relatively small molecules as compare with classic drugs which give benefits towards permeability of blood brain barrier (BBB). The purpose of this review provide a comprehensive overview of the use of microbubbles and echogenic liposomes for the delivery of bioactive gasses.

Pharmacology of Gases

Oxygen (O2)
The development and growth of multicellular organisms oxygen is play essential role,it administrated to prevent hypoxic injury, the ability to sense and respond to changes in oxygen is important for the survival of prokaryotic and eukaryotic organisms. According to report 60% of solid tumor contain hypoxic tissue and its associated with radiation therapy, adverse effects of classic drugs. Resulting, Tumor hypoxia leads to poor prognosis in cancer’s patients, which is one of the deadly human cancer. Hypoxia-inducible responses are potentially regulated in normal embryonic development and are dysregulated in a tumor hypoxia. In case of respiratory failure (ARDS) require higher amount of FiO2 (fraction of inspired oxygen) with mechanical ventilation to maintain constant level of oxygenation. Oxygen rapidly covert carboxyhemoglobin to oxyhemoglobin to avoid CO2 poisoning, it dissolves in plasma thereby causing relief hypoxia to tissue. In case of anemia. There is decrease in level of O2 supply and there is a need to restore oxygen delivery to tissues For this purpose, significant efforts have been made toward developing artificial blood substitutes. These are typically perfluorocarbon emulsions or hemoglobin based oxygen carriers. Oxygen therapy is of value in cases of cerebrovascular accidents where good oxygenation of hypoxic areas of brain. O2 inhalation is also beneficial in thermotoxicosis and hyperthermia.

Nitric oxide (NO)

It is colorless, poisonous gas which causes serious air pollutant. Biologically NO produced from L-arginine by iNOS and endothelial NOS. It is an important signaling molecule in the body of mammals. NO plays vital role in the vascular homeostasis by its potent vasoregulatory and immunodulatory characteristics. NO stimulate sGC(soluble guanylate cyclase) and increase cGMP content in smooth muscle cells propagating relaxation of vascular tone and vasodilatation and it is also responsible for blood vessel dilation(regulation of platelet activity), which increase tissue blood supply and diminish the inflammatory response leading protection of tissue from oxidative insults. Inhalation of NO prevent graft injury due to ischemia or reperfusion injury after human lungs and liver transplantation.

Hydrogen Sulfide (H2S)

Hydrogen sulfide (H2S) is a colorless, toxic and flammable gas. Hydrogen sulfide is biologically synthesized from L-cysteine, a product methionine, by CBS and cyctathione-γ-lyase. Methionine adenosyltransferase (MAT) converts methionine to homocystine. CBS catalyses thehomocystine to cystathionine conversion. CSE, subsequently, converts cystathionine to L-cysteine, which is further metabolized to hydrogen sulfide by CBS and CSE. H2S help regulate body temperature and metabolic activity at physiological concentrations. H2S affect on cardiovascular system possibly through modulation of K+-ATP channel opening or as a cellular messenger molecule involved vascular flow regulation. Hydrogen sulphide has the potential to act as an antioxidant inhibitor of peroxy nitrite mediated processes via activation of N-methyl-D-aspartate receptor which shield cultured neurons from oxidative damage by increasing levels of glutathione, an antioxidant enzyme,H2S can induce upregulation of HO-1, anti-inflammatory and cytoprotective genes .H2S give antioxidant by its effects on cytochrome c oxidase and mitochondrial functions, while its effects on gene expression may be related to actions on the the NFkB and ERK pathways, H2S protect cardiac system from oxidative injury

Methane(CH4)

It was previously assumed that methane is not utilized by humans, so it is excreted either as flatus, or it traverses the intestinal mucosa and is absorbed into the systemic circulation and excreted unchanged through the lungs as per research methane could exert anti-inflammatory effects. methanogens in the colon can use CO2 and H2 to produce methane as a by-product. Methane gas is produced by enteric bacteria in 30–60% of humans. Pulmonary methane excretion ranged from undetectable to 0.66 ml/min, and 20% of total methane produced was excreted via the lungs(basis on LBT). The therapeutic effect of methane may be confirmed in animal models to conform whether the protective effect of methane is species-specific. Inhalation of methane acts more rapidly, may be suitable for defense against acute oxidative stress. However, it may be impractical for daily application for disease prevention due to its flammability and difficulty to transport. Thus, normal saline rich in methane may be prepared as an injection which may be portable, easily administered and safe.

Helium(He)

Helium is a very light, odorless, tasteless, and colorless noble gas with a strong safety profile and multiple applications. Because of unique physical properties (MP,BP, Density) helium used in many purposes. The high thermal conductivity of helium results in lower body temperature when the body is immersed in helium, which could result in decreased metabolism and decreased energy expenditure [5]. In humans, breathing helium for short periods has not been shown to induce hypothermia. Clinical application of helium is in various areas

Carbon Monoxide(CO)

It is colorless, odorless initially consider as poison, avidly binds to hemoglobin and forms carboxyhemoglobin. CO is endogenously and physiologically generated in mammalian cells via the catabolism of heme in the rate-limiting step by hemeoxygenase systems. application of CO to animals at low concentrations approximating cigarette-smoke exposure caused no apparent lung pathology. Carbon monoxide may prevent the degradation of heme proteins by binding to the heme moiety. The functions treated in UW with CO showed better renal functions and fewer inflammatory events. Ex vivo organ-targeted CO delivery during cold storage prevents CYP breakdown during the ischemia/reperfusion process.

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